The long-term objective is to determine the impact of environmental toxicants on the peripheral and central olfactory tissues, and the role of xenobiotic exposure in the etiology of anosmia and other diseases concerning the nasal cavity. Our focus continues to be on the function of cytochrome P450 (CYP or P450) enzymes in various nasal tissues, with an emphasis on the mechanisms of tissue-specific toxicity and molecular approaches to risk assessment. Studies in the current funding period and those proposed for the new funding cycle involve two nasal structures, the olfactory mucosa (OM) and the lateral nasal gland (LNG). The OM, where olfactory receptor neurons (ORNs) reside, is the main olfactory sensory organ. The lateral nasal gland (LNG), which secretes odorant binding proteins and immunoglobulin A to the nasal mucus, is an important organ for the ability to detect odorant signals and for the maintenance of the OM. Both OM and LNG are target organs for toxic damage by numerous xenobiotic compounds. The studies in this and other laboratories in the past >20 years have built a large body of knowledge regarding the expression, regulation, in vitro function, and genetic polymorphisms of various nasal P450 enzymes. Our recent studies, including those in the current funding cycle, have centered on the establishment and characterization of novel transgenic mouse models that can be used for the determination of the in vivo role of P450 enzymes in xenobiotic-induced olfactory toxicity. In the proposed studies, we will take advantage of the novel tools, as well as exciting preliminary data, obtained in the current funding cycle, 1) to further determine the capability of human OM P450 enzymes to metabolize various nasal toxicants in vitro and in vivo (in "humanized" mouse models);2) to identify mechanisms that underlie the ability of certain toxicants, such as the herbicide dichlobenil, to cause irreversible neurodegeneration to the OM;and 3) to determine the mechanisms that influence resistance to xenobiotic toxicity in the LNG. PUBLIC HEALTH RELEVANCE: The proposed studies, which deal with fundamental issues in xenobiotic metabolism and tissue-selective chemical toxicity, will impact risk assessment of potential olfactory toxicants in humans. The outcome of the proposed studies will provide the biochemical basis for identifying human individuals with increased susceptibility to a given toxicant. The anticipated findings will also be important for our ability to predict not only which chemical entity will cause irreversible OM degeneration or LNG toxicity in animal models, but also whether such permeant, deleterious health effects could occur in humans.